There is convincing evidence that cellular prooxidant states--that is, increased concentrations of active oxygen and organic peroxides and radicals--can promote initiated cells to neoplastic growth. Prooxidant states can be caused by different classes of agents, including hyperbaric oxygen, radiation, xenobiotic metabolites and Fenton-type reagents, modulators of the cytochrome P-450 electron-transport chain, peroxisome proliferators, inhibitors of the antioxidant defense, and membrane-active agents. Many of these agents are promoters or complete carcinogens. They cause chromosomal damage by indirect action, but the role of this damage in carcinogenesis remains unclear. Prooxidant states can be prevented or suppressed by the enzymes of the cellular antioxidant defense and low molecular weight scavenger molecules, and many antioxidants are antipromoters and anticarcinogens. Finally, prooxidant states may modulate the expression of a family of prooxidant genes, which are related to cell growth and differentiation, by inducing alterations in DNA structure or by epigenetic mechanisms, for example, by polyadenosine diphosphate-ribosylation of chromosomal proteins.

https://science.sciencemag.org/content/sci/227/4685/375.full.pdf

Prooxidant states and tumor promotion.

Activation of a cytosolic ADP-ribosyltransferase by nitric oxide-generating agents.

The nuclear enzyme ADP-ribosyl transferase (ADPRT) catalyses the formation of poly(ADP-ribose)-modified chromatin proteins from NAD+ (refs 1–5) and is entirely dependent on DNA6 containing nicks7–11. Nuclear ADPRT activity is required for efficient DNA excision repair12,13, probably because it regulates DNA ligase activity14. Indirect evidence has suggested that ADPRT activity may also be involved in control of gene expression and cell differentiation15–21. We report here an obligatory involvement of ADPRT activity in the differentiation of muscle cells. Inhibitors of ADPRT activity reversibly inhibit both fusion of myoblasts to form multi-nucleate muscle fibres and the differentiation-specific increase in creatine phos-phokinase (CPK) activity. These two markers of differentiation can also be reversibly inhibited by depriving the cells of nicotinamide and thus lowering their cellular NAD content. Specific gene expression sometimes requires gene rearrangements or DNA transposition; this implies that DNA strand-breaking and rejoining might be involved in gene expression. We also describe the appearance during cytodifferentiation of single-strand DNA breaks which are not due to a general deficiency in DNA repair.

DNA strand breaks and ADP-ribosyl transferase activation during cell differentiation.

Oxidative stress as a causal factor in differentiation and aging: a unifying hypothesis

In the past five years, poly(ADP-ribosyl)ation has developed greatly with the help of molecular biology and the improvement of biochemical techniques. In this article, we describe the physico-chemical properties of the enzymes responsible for the synthesis and degradation of poly(ADP-ribose), respectively poly(ADP-ribose) polymerase and poly(ADP-ribose) glycohydrolase. We then discuss the possible roles of this polymer in DNA repair and replication as well as in cellular differentiation and transformation. Finally, we put forward various hypotheses in order to better define the function of this polymer found only in eucaryotes. (Mol Cell Biochem122: 171–193, 1993)

Molecular and biochemical features of poly (ADP-ribose) metabolism

The nuclear enzyme ADP-ribosyltransferase (ADPRT) catalyses the postsynthetic modification of chromatin proteins1 The significance of [ADP-ribose]n-modified chromatin proteins for the regulation of chromatin function is not understood1 Recently, [ADP-ribose]n biosynthesis has been demonstrated to participate in the repair of some types of DNA damage2–4 Here we demonstrate that another function of [ADP-ribose]n biosynthesis is related to the regulation of the expression of two fetal functions of cultured hepatocytes—the K-type (III) isozyme of pyruvate kinase, and γ-glutamyltranspeptidase, which is also a marker of early neoplastic transformation of liver cells5

Yu-Zhu He

Papers

Effects of altered [ADP-ribose]n metabolism on expression of fetal functions by adult hepatocytes